Progressive scarring (fibrosis) is a pathological feature of many chronic inflammatory diseases, and is an important cause of morbidity and mortality worldwide. Fibrosis is characterized by the accumulation of excess extracellular matrix components (e.g., collagen, fibronectin) that forms fibrous connective tissue in and around an inflamed or damaged tissue. Fibrosis may cause overgrowth, hardening, and/or scarring that disrupts the architecture of the underlying organ or tissue. While controlled tissue remodeling and scarring is part of the normal wound healing process promoted by transdifferentiation of fibroblasts into myofibroblasts, excessive and persistent scarring due to severe or repetitive injury or dysregulated wound healing (e.g., persistence of myofibroblasts) can eventually result in permanent scarring, organ dysfunction and failure, and even death.
Fibrotic changes can occur in vascular disorders (e.g., peripheral vascular disease, cardiac disease, cerebral disease) and in all main tissue and organ systems (e.g., lung, liver, kidney, heart, skin). Fibrotic disorders include a wide range of clinical presentations, including multisystemic disorders, such as systemic sclerosis, multifocal fibrosclerosis, and organ-specific disorders, such as pulmonary, liver, and kidney fibrosis (Rosenbloom et al., Ann. Intern. Med. 152:159, 2010; Wynn, Nat. Rev. Immunol. 4:583, 2004). While the etiology and causative mechanisms of individual fibrotic disorders may vary (e.g., ischemic event, exposure to a chemical, radiation, or infectious agent) and are poorly understood, they all share the common feature of abnormal and excessive deposition of extracellular matrix in affected tissues (Wynn and Ramalingam, Nat. Med. 18:1028, 2012).
There are no effective therapies on the market today in the U.S. for treating or preventing fibrotic disorders. Current treatments generally target the inflammatory cascade that contribute to the progression of fibrosis and may temporarily improve symptoms, but are not effective in the long run (Wynn, 2004). Furthermore, the lack of biomarkers for assessing fibrosis progression or regression and therapeutic response has impeded rapid clinical screening of potential therapeutics (Schuppan and Pinzani, J. Hepatol. 56: S66, 2012; Castro and Jimenez, Biomark Med. 4:133, 2010).
There is clearly a need in the art for new, effective methods of treating or preventing fibrotic disorders and for identifying biomarkers for use in developing therapeutic agents and assessing therapeutic response. The present disclosure meets such needs, and further provides other related advantages.